rs1801260

Positions:

• chr4-55435202-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004898.4(CLOCK):​c.*213T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 587,320 control chromosomes in the GnomAD database, including 21,892 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.25 (4961 hom., cov: 32)
  • Exomes 𝑓: 0.27 (16931 hom.)
• Consequence: CLOCK NM_004898.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.802

Genes affected

CLOCK (HGNC:2082): (clock circadian regulator) The protein encoded by this gene plays a central role in the regulation of circadian rhythms. The protein encodes a transcription factor of the basic helix-loop-helix (bHLH) family and contains DNA binding histone acetyltransferase activity. The encoded protein forms a heterodimer with ARNTL (BMAL1) that binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Polymorphisms in this gene may be associated with behavioral changes in certain populations and with obesity and metabolic syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMEM165 (HGNC:30760): (transmembrane protein 165) This gene encodes a predicted transmembrane protein with a perinuclear Golgi-like distribution in fibroblasts. Mutations in this gene are associated with the autosomal recessive disorder congenital disorder of glycosylation, type IIk. Knockdown of this gene's expression causes decreased sialylation in HEK cells and suggests this gene plays a role in terminal Golgi glycosylation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLOCK	NM_004898.4	c.*213T>C		3_prime_UTR_variant	23/23	ENST00000513440.6	NP_004889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLOCK	ENST00000513440.6	c.*213T>C		3_prime_UTR_variant	23/23	1	NM_004898.4	ENSP00000426983	P1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37470 AN: 152032 Hom.: 4955 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.0993

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.246

GnomAD4 exome AF: 0.272 AC: 118169 AN: 435170 Hom.: 16931 Cov.: 4 AF XY: 0.278 AC XY: 63693 AN XY: 229406

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.231

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.246 AC: 37495 AN: 152150 Hom.: 4961 Cov.: 32 AF XY: 0.252 AC XY: 18704 AN XY: 74362

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.0991

Gnomad4 SAS AF: 0.371

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.245

Alfa AF: 0.268 Hom.: 9691

Bravo AF: 0.226

Asia WGS AF: 0.261 AC: 908 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.3
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1801260; hg19: chr4-56301369; COSMIC: COSV59401751;